Transgender children and adolescents are a poorly understood and a distinctly understudied population in the United States. The limited available data suggest that transgender youth who are gender dysphoric (persistently distressed about gender incongruence) are at increased risk for negative mental and medical health outcomes including anxiety, depression, HIV acquisition, suicide, and substance use compared to their peers. Therefore, medical intervention is aimed at alleviating gender dysphoria and ameliorating potential negative outcomes. Existing strategies for treating transgender youth depend on the developmental stage at which these youth present for care. For those transgender youth that present for care in the early stages of pubertal development, treatment is aimed at suppressing their endogenous puberty in order to avoid the development of undesired secondary sexual characteristics that intensify the distress associated with gender incongruence. For those youth in later stages of puberty, the goal of treatment is to use cross-sex hormones in order to induce the development of desired secondary sexual characteristics that bring the body into closer alignment with the youth's internal sense of gender. In 2011, the Institute of Medicine emphasized a clear need for the development of evidence-based and rigorous research aimed at understanding the health implications of hormone use in transgender individuals. The proposed study networks four academic sites around the country (Children's Hospital Los Angeles/University of Southern California, Boston Children's Hospital, Lurie Children's Hospital of Chicago/Northwestern University, and University of California San Francisco) with dedicated transgender youth clinics to conduct a multi-site observational study examining the physiological and psychosocial outcomes of existing medical treatment protocols for transgender youth with gender dysphoria. The study will include two groups of gender dysphoric youth: one in the earliest stages of pubertal development to assess the impact of puberty suppression, and one in later stages of pubertal development to assess the impact of cross-sex hormones for gender transition. Specifically, in the earlier pubertal cohort (Tanner stages 2-3; n=80) the study will evaluate the impact on mental health, psychological well-being, physiologic parameters and bone health as well as document safety of GnRH agonists administered for puberty suppression. In the later pubertal cohort (Tanner stages 4-5; n=200) the study will evaluate the impact on mental health, psychological well-being, and metabolic/physiologic parameters, as well as document the safety of cross-sex hormones administered for gender transition. This multi-center study will be the first in the U.S. to evaluate longitudinal outcomes of medical treatment for transgender youth and will provide essential evidence-based data on the physiological and psychosocial effects and safety of treatments currently used for transgender youth.